In vivo examination of hydroxyurea and the novel ribonucleotide reductase inhibitors trimidox and didox in combination with the reverse transcriptase inhibitor abacavir: suppression of retrovirus-induced immunodeficiency disease.

Abstract	Inhibition of ribonucleotide reductase (RR) has gained attention as a potential strategy for HIV-1 therapy through the success of hydroxyurea (HU) to potentiate the activity of the nucleoside reverse transcriptase inhibitor (NRTI) didanosine (ddI) in clinical trials. However, the use of HU has been limited by its development of hematopoietic toxicity. In this study, the novel RR inhibitors didox (DX; 3,4-dihydroxybenzohydroxamic acid), and trimidox (TX; 3,4,5-trihydroxybenzamidoxime) were evaluated along with HU for anti-retroviral efficacy in LPBM5-induced retro-viral disease (MAIDS) both as monotherapeutic regimens and in combination with the guanine containing NRTI abacavir (ABC). Anti-retroviral drug efficacy was determined by measuring inhibition of splenomegaly, hypergammaglobulinemia, and splenic levels of proviral DNA. In this study, all RRIs tested showed the ability to improve the efficacy of ABC in the MAIDS model by reducing splenomegaly, hypergammaglobulinemia, and splenic proviral DNA levels.
Authors	L Ryan Sumpter, Mohammed S Inayat, Erin E Yost, William Duvall, Espen Hagan, Christopher N Mayhew, Howard L Elford, Vincent S Gallicchio
Journal	Antiviral research (Antiviral Res) Vol. 62 Issue 3 Pg. 111-20 (Jun 2004) ISSN: 0166-3542 [Print] Netherlands
PMID	15130534 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	3,4,5-trihydroxybenzamidoxime Antiviral Agents Benzamidines Dideoxynucleosides Hydroxamic Acids Ribonucleotide Reductases 3,4-dihydroxybenzohydroxamic acid abacavir Hydroxyurea
Topics	Animals Antiviral Agents (pharmacology, therapeutic use) Benzamidines (therapeutic use) Bone Marrow Cells (drug effects) Dideoxynucleosides (therapeutic use) Disease Models, Animal Drug Therapy, Combination Hematopoietic Stem Cells (drug effects) Hydroxamic Acids (therapeutic use) Hydroxyurea (adverse effects, chemistry, therapeutic use) Mice Mice, Inbred C57BL Murine Acquired Immunodeficiency Syndrome (blood, drug therapy, immunology, pathology) Ribonucleotide Reductases (antagonists & inhibitors) Spleen (pathology) Splenomegaly

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